Substituted urea compounds useful in pain management

ABSTRACT

Compounds of general formula Iare disclosed and claimed in the present application, as well as their pharmaceutically acceptable salts, pharmaceutical compositions comprising the novel compounds and their use in therapy, in particular in the management of pain.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application represents U.S. national stage of internationalapplication PCT/SE99/01077 which has an international filing date ofJun. 16, 1999 and which was published in English under Article 21(2) ofthe PCT on Dec. 29, 1999 as No. 9/67206. The international applicationclaims priority to Swedish application 9802208-0, filed on Jun. 22,1998.

FIELD OF THE INVENTION

The present invention is related to novel compounds, to a process fortheir preparation, their use and pharmaceutical compositions comprisingthe novel compounds. The novel compounds are useful in therapy, and inparticular for the treatment of pain.

BACKGROUND AND PRIOR ART

The δ receptor has been identified as having a role in many bodilyfunctions such as circulatory and pain systems. Ligands for the δreceptor may therefore find potential use as analgesics, and/or asantihypertensive agents. Ligands for the δ receptor have also been shownto possess immunomodulatory activities.

The identification of at least three different populations of opioidreceptors (μ, δ and κ) is now well established and all three areapparent in both central and peripheral nervous systems of many speciesincluding man. Analgesia has been observed in various animal models whenone or more of these receptors has been activated.

With few exceptions, currently available selective opioid δ ligands arepeptidic in nature and are unsuitable for administration by systemicroutes. Some non-peptidic δ antagonists have been available for sometime (see Takemori and Portoghese, 1992, Ann. Rev. Pharmacol. Tox., 32:239-269. for review). These compounds, e.g. naltrindole, suffer fromrather poor (i.e., <10-fold) selectivity for the δ receptor vs. μreceptor binding and exhibit no analgesic activity, a fact whichunderscores the need for the development of highly selectivenon-peptidic δ ligands.

Thus, the problem underlying the present invention was to find newanalgesics having improved analgesic effects, but also with an improvedside-effect profile over current μ agonists and potential oral efficacy.

Analgesics that have been identified and are existing in the prior arthave many disadvantages in that they suffer from poor pharmacokineticsand are not analgesic when administered by systemic routes. Also, it hasbeen documented that preferred compounds, described within the priorart, show significant convulsive effects when administered systemically.

The problem mentioned above has now been solved by developing novel1,4-substituted cyclohexyl compounds, as will be described below.

OUTLINE OF THE INVENTION

The novel compounds according to the present invention are defined bythe general formula I

wherein

m and n is each and independently an integer of from 0-3, and one ormore of the hydrogens in such an alkylene-chain may optionally besubstituted by anyone of C₁-C₆ alkyl C₁-C₆ alkoxy or hydroxy; or

one or more of the methylene groups may optionally be substituted by aheteroatom such as O, N or S;

R¹ is selected from hydrogen, a branched or straight C₁-C₆ alkyl, C₂-C₆alkenyl, C₃-C₈ cycloalkyl, C₄-C₈(alkyl-cycloalkyl) wherein the alkyl isC₁-C₂ alkyl and the cycloalkyl is C₃-C₆ cycloalkyl;

R² is selected from any of

(i) hydrogen;

(ii) a straight or branched C₁-C₆ alkyl C₂-C₆ alkenyl or C₂-C₆alkynyl;

(iii) —[(CH₂)_(q)— aryl];

(iv) —((CH₂)_(r)-heteroaryl) where the heteroaryl has from 5 to 10 atomsand the heteroatom is selected from any of S, N and O;

 and wherein the heteroaryl may optionally and independently besubstituted by 1 or 2 substituents Y where each Y is as defined below;and wherein q and r is each and independently an integer of from 0 to 3;

(v) C₃-C₁₀ cycloalkyl, optionally comprising one or more unsaturationsand optionally susbtituted by one or more heteroaryl(s) where theheteroaryl has from 5 to 10 atoms and the heteroatom being selected fromany of S, N and O;

 and wherein the aryl and heteroaryl may optionally and independently besubstituted by 1 or 2 substituents Y where each Y is as defined below;

(vi) C₆-C₁₀ aryl, optionally and independently substituted by one ormore heteroaryl(s) having from 5 to 10 atoms and the heteroatom(s) beingselected from any of S, N and O and wherein the heteroaryl mayoptionally and independently be substituted by 1 or 2 substituents Ywherein each Y is as defined below;

(vii) heteroaryl having from 5 to 10 atoms and the heteroatom beingselected from any of S, N and O; wherein the aryl and heteroaryl mayoptionally and independently be substituted by 1 or 2 substituents Ywherein each Y is as defined below;

or

R¹ and R² may optionally form a heterocyclic ring, which may optionallybe saturated or unsaturated;

R³ is selected from anyone of

(i) hydrogen;

(ii) a straight or branched C₁-C₆ alkyl, C₂-C₆ alkenyl or C₂-C₆ alkynyl;

(iii) C₆-C₁₀ arylalkyl, wherein the aryl may optionally be substitutedby one or more heteroaryl(s) having from 5 to 10 atoms and theheteroatom being selected from any of S, N and O; and wherein the aryland heteroaryl may optionally and independently be substituted by 1 or 2substituents Y wherein each Y is as defined below;

(iv) heteroaryl-(C₅-C₁₀alkyl) where the heteroaryl has from 5 to 10atoms, the heteroatom being selected from any of S, N and O, and whereinthe heteroaryl may optionally and independently be substituted by 1 or 2substituents Y where each Y is as defined below;

(v) C₃-C₁₀ cycloalkyl, optionally comprising one or more unsaturationsand optionally substituted by one or more heteroaryl(s) having from 5 to10 atoms and the heteroatom being selected from any of S, N and O, andwherein the aryl and heteroaryl may optionally and independently besubstituted by 1 or 2 substituents Y where each Y is as defined below;

(vi) —[C₃-C₆ cycloalkyl-(CH₂)_(q)] wherein q is an integer of from 1 to3;

R⁴ is selected from

(i) hydrogen;

(ii) a straight or branched C₁-C₆ alkyl, C₂-C₆ alkenyl or C₂-C₆ alkynyl;

(iii) C₆-C₁₀ arylalkyl, wherein the aryl may optionally be substitutedby one or more heteroaryl(s) having from 5 to 10 atoms and theheteroatom being selected from any of S, N and O; and wherein the aryland heteroaryl may optionally and independently be substituted by 1 or 2substituents Y wherein each Y is as defined below;

(iv) heteroaryl-(C₅-C₁₀alkyl) where the heteroaryl has from 5 to 10atoms, the heteroatom being selected from any of S, N and O, and whereinthe heteroaryl may optionally and independently be substituted by 1 or 2substituents Y where each Y is as defined below;

(v) C₃-C₁₀ cycloalkyl, optionally comprising one or more unsaturationsand optionally susbtituted by one or more heteroaryl(s) where theheteroaryl has from 5 to 10 atoms and the heteroatom being selected fromany of S, N and O;

 and wherein the aryl and heteroaryl may optionally and independently besubstituted by 1 or 2 substituents Y where each Y is as defined below;

(vi) C₆-C₁₀ aryl, optionally and independently substituted by one ormore heteroaryl(s) having from 5 to 10 atoms and the heteroatom(s) beingselected from any of S, N and O and wherein the heteroaryl mayoptionally and independently be substituted by 1 or 2 substituents Ywherein each Y is as defined below;

(vii) heteroaryl having from 5 to 10 atoms, the heteroatom beingselected from any of S, N and O; wherein the heteroaryl may optionallyand independently be substituted by 1 or 2 substituents Y wherein each Yis as defined below;

R⁵ is selected from anyone of

(i) hydrogen;

(ii) a straight or branched C₁-C₆ alkyl, C₂-C₆ alkenyl or C₂-C₆ alkynyl;

(iii) C₆-C₁₀ arylalkyl, wherein the aryl may optionally be substitutedby one or more heteroaryl(s) having from 5 to 10 atoms and theheteroatom being selected from any of S, N and O; and wherein the aryland heteroaryl may optionally and independently be substituted by 1 or 2substituents Y wherein each Y is as defined below;

(iv) heteoaryl-(C₅-C₁₀ alkyl), where the heteroaryl has from 5 to 10atoms and the heteroatom being selected from any of S, N and O, andwherein the aryl and heteroaryl may optionally and independently besubstituted by 1 or 2 substituents Y where each Y is as defined below;

(v) C₃-C₁₀ cycloalkyl, optionally comprising one or more unsaturationsand optionally substituted by one or more heteroaryl(s) having from 5 to10 atoms and the heteroatom being selected from any of S, N and O, andwherein the aryl and heteroaryl may optionally and independently besubstituted by 1 or 2 substituents Y where each Y is as defined below;

(vi) C₅-C₁₀ aryl, optionally and independently substituted by one ormore heteroaryl(s) having from 5 to 10 atoms and the heteroatom(s) beingselected from any of S, N and O and wherein the heteroaryl mayoptionally and independently be substituted by 1 or 2 substituents Ywherein each Y is as defined below;

(vii) heteroaryl having from 5 to 10 atoms, the heteroatom beingselected from any of S, N and O; wherein the heteroaryl may optionallyand independently be substituted by 1 or 2 substituents Y wherein each Yis as defined below;

wherein

R⁷, R⁸, R⁹, R¹⁰ and R¹¹ is each and independently selected from

(a) hydrogen;

(b) a straight or branched C₁-C₆ alkyl, C₂-C₆ alkenyl or C₂-C₆ alkynyl;

(c) C₆-C₁₀ arylalkyl, wherein the aryl may optionally be substituted byone or more heteroaryl(s) having from 5 to 10 atoms and the heteroatombeing selected from any of S, N and O; and wherein the aryl andheteroaryl may optionally and independently be substituted by 1 or 2substituents Y wherein each Y is as defined below;

(d) heteroaryl-(C₅-C₁₀alkyl), where the heteroaryl has from 5 to 10atoms, the heteroatom being selected from any of S, N and O, and whereinthe heteroaryl may optionally and independently be substituted by 1 or 2substituents Y where each Y is as defined above;

(e) C₃-C₁₀ cycloalkyl, optionally comprising one or more unsaturationsand optionally susbtituted by one or more heteroaryl(s) where theheteroaryl has from 5 to 10 atoms and the heteroatom being selected fromany of S, N and O;

 and wherein the aryl and heteroaryl may optionally and independently besubstituted by 1 or 2 substituents Y where each Y is as defined below;

(f) C₆-C₁₀ aryl, optionally and independently substituted by one or moreheteroaryl(s) having from 5 to 10 atoms and the heteroatom(s) beingselected from any of S, N and O and wherein the heteroaryl mayoptionally and independently be substituted by 1 or 2 substituents Ywherein each Y is as defined below;

or

R⁴ and R⁵ may optionally form a heterocyclic ring, which may optionallybe saturated or unsaturated;

Y is each and independently selected from any of hydrogen, CH₃;—(CH₂)_(p1)CF₃; halogen; C₁-C₃ alkoxy; hydroxy; —NO₂; —OCF₃;—CONR^(a)R^(b); —COOR^(a); —COR^(a); —(CH₂)_(p2)NR^(a)R^(b);—(CH₂)_(p3)CH₃, (CH₂)_(p4)SOR^(a)R^(b); —(CH₂)_(p5)SO₂R^(a);—(CH₂)_(p6)SO₂NR^(a); C₄-C₈(alkyl-cycloalkyl) wherein alkyl is C₁-C₂alkyl and cycloalkyl is C₃-C₆ cycloalkyl; 1 or 2 heteroaryl(s) havingfrom 5 to 10 atoms and the heteroatom(s) being selected from any of S, Nand O; and oxides such as N-oxides or sulfoxides; and wherein

R^(a) and R^(b) is each and independently selected from hydrogen, abranched or straight C₁-C₆ alkyl, C₁-C₆ alkenyl, C₃-C₈ cycloalkyl; andwherein

p1, p2, p3, p4, p5 and p6 is each and independently 0, 1 or 2.

Within the scope of the invention are also pharmaceutically acceptablesalts of the compounds of the formula (I), as well as isomers, hydrates,isoforms and prodrugs thereof.

Examples of heterocyclic ring systems which ma y be formed by R²and R³together include but are not limited to azeridine, pyrrolidine,piperidine, azepine, azocine, their hydrogenated or dehydrogenatedderivatives, their aminoderivatives and other aza-heterocycle moietiesand their derivatives, such as dihydroimidazoles, di-, tetra- andhexahydropyrimidines and the like.

Preferred compounds according to the invention are compounds of theformula I wherein

m=n=1

R¹ is selected from hydrogen or C₁-C₆ alkyl;

R² is selected from

(i) hydrogen;

(ii) C₆-C₁₀ aryl, optionally and independently substituted by one ormore heteroaryl(s) having from 5 to 10 atoms and the heteroatom(s) beingselected from any of S, N and O and wherein the heteroaryl mayoptionally and independently be substituted by 1 or 2 substituents Ywherein each Y is as defined above;

(iii) C₁-C₆ alkyl; or

(iv) C₃-C₁₀ cycloalkyl, optionally comprising one or more unsaturationsand optionally substituted by one or more heteroaryl(s) having from 5 to10 atoms and the heteroatom being selected from any of S, N and O, andwherein the aryl and heteroaryl may optionally and independently besubstituted by 1 or 2 substituents Y where each Y is as defined above;

R³ is selected from

(i) hydrogen;

(ii) C₆-C₁₀ arylalkyl, wherein the aryl may optionally be substituted byone or more heteroaryl(s) having from 5 to 10 atoms and the heteroatombeing selected from any of S, N and O; and wherein the aryl andheteroaryl may optionally and independently be substituted by 1 or 2substituents Y wherein each Y is as defined above;

(iii) —[C₃-C₆ cycloalkyl-(CH₂)_(q)] wherein q is an integer of from 1 to3;

R⁴ is hydrogen;

R⁵ is selected from anyone of

(i) hydrogen;

(ii) a straight or branched C₁-C₆ alkyl, C₂-C₆ alkenyl or C₂-C₆ alkynyl;

(iii) C₆-C₁₀ arylalkyl, wherein the aryl may optionally be substitutedby one or more heteroaryl(s) having from 5 to 10 atoms and theheteroatom being selected from any of S, N and O; and wherein the aryland heteroaryl may optionally and independently be substituted by 1 or 2substituents Y wherein each Y is as defined above;

(iv) heteroaryl-(C₅-C₁₀alkyl) where the heteroaryl has from 5 to 10atoms, the heteroatom being selected from any of S, N and O, and whereinthe heteroaryl may optionally and independently be substituted by 1 or 2substituents Y where each Y is as defined above;

(v) C₃-C₁₀ cycloalkyl, optionally comprising one or more unsaturationsand optionally substituted by one or more heteroaryl(s) having from 5 to10 atoms and the heteroatom being selected from any of S, N and O, andwherein the aryl and heteroaryl may optionally and independently besubstituted by 1 or 2 substituents Y where each Y is as defined above;

(vi) heteroaryl having from 5 to 10 atoms, the heteroatom being selectedfrom any of S, N, and O; wherein the heteroaryl may optionally andindependently be substituted by 1 or 2 substituents Y wherein each Y isas defined above;

wherein

R⁷, R⁸, R⁹, R¹⁰ and R¹¹ is each and independently selected from

(a) hydrogen;

(b) a straight or branched C₁-C₆ alkyl, C₂-C₆ alkenyl or C₂-C₆ alkynyl;

(c) C₆-C₁₀ arylalkyl, wherein the aryl may optionally be substituted byone or more heteroaryl(s) having from 5 to 10 atoms and the heteroatombeing selected from any of S, N and O; and wherein the aryl andheteroaryl may optionally and independently be substituted by 1 or 2substituents Y wherein each Y is as defined above;

(d) heteroaryl-(C₅-C₁₀alkyl), where the heteroaryl has from 5 to 10atoms, the heteroatom being selected from any of S, N and O, and whereinthe heteroaryl may optionally and independently be substituted by 1 or 2substituents Y where each Y is as defined above;

(e) C₃-C₁₀ cycloalkyl, optionally comprising one or more unsaturationsand optionally susbtituted by one or more heteroaryl(s) where theheteroaryl has from 5 to 10 atoms and the heteroatom being selected fromany of S, N and O; and wherein the aryl and heteroaryl may optionallyand independently be substituted by 1 or 2 substituents Y where each Yis as defined above;

(f) C₆-C₁₀ aryl, optionally and independently substituted by one or moreheteroaryl(s) having from 5 to 10 atoms and the heteroatom(s) beingselected from any of S, N and O and wherein the heteroaryl mayoptionally and independently be substituted by 1 or 2 substituents Ywherein each Y is as defined above;

or

R⁴ and R⁵ may optionally form a heterocyclic ring, which may optionallybe saturated;

Particularly preferred compounds according to the invention arecompounds of the formula I wherein

m=n=1

R¹ is selected from

(i) hydrogen; and

(ii) methyl;

R² is selected from

(i) hydrogen;

(ii) phenyl;

(iii) C₁-C₃ alkyl;

(iv) C₃-C₆ cycloalkyl;

or

R¹ and R² taken together may form a ring of from 4 to 6 atoms selectedfrom C, N and O;

R³ is selected from

(i) hydrogen;

(ii) —CH₂-cyclohexyl;

(iii) —CH₂-phenyl, optionally substituted by one or more halogens;

(iv) —CH₂-naphthyl;

R⁴ is hydrogen;

R⁵ is selected from

(i) hydrogen;

(iv) heteroaryl-(C₅-C₁₀), where the heteroaryl has from 5 to 10 atoms,the heteroatom being selected from any of S, N and O, and wherein theheteroaryl may optionally and independently be substituted by 1 or 2sustituents Y where each Y is as defined above;

By “halogen” we mean chloro, fluoro, bromo and iodo.

By “aryl” we mean an aromatic ring having 6 or 10 carbon atoms, such asphenyl and naphthyl.

By “heteroaryl” we mean an aromatic ring in which one or more of thefrom 5-10 atoms in the ring are elements other than carbon, such as N, Sand O.

By “isomers” we mean compounds of the formula (I), which differ by theposition of their functional group and/or orientation. By “orientation”we mean stereoisomers, diastereoisomers, regioisomers and enantiomers.

By “isoforms” we mean compounds of the formula I which differ in therelative physical arrangement of molecules by crystal lattice, such thatisoforms refer to various crystalline compounds and amorphous compounds.

By “prodrug” we mean pharmacologically acceptable derivatives, e.g.esters and amides, such that the resulting biotransformation product ofthe derivative is an active form of the drug. The reference by Goodmanand Gilmans, The Pharmacological basis of Therapeutics, 8th ed.,McGraw-Hill, Int. Ed. 1992, “Biotransformation of Drugs, p. 13-15,describing prodrugs generally, is hereby incorporated by reference.

The novel compounds of the present invention are useful in therapy,especially for the treatment of various pain conditions such as chronicpain, acute pain, cancer pain, pain caused by rheumatoid arthritis,migraine, visceral pain etc. This list should however not be interpretedas exhaustive.

Compounds of the invention are useful as immunomodulators, especiallyfor autoimmune diseases, such as arthritis, for skin grafts, organtransplants and similar surgical needs, for collagen diseases, variousallergies, for use as anti-tumour agents and anti viral agents.

Compounds of the invention are useful in disease states wheredegeneration or dysfunction of opioid receptors is present or implicatedin that paradigm. This may involve the use of isotopically labelledversions of the compounds of the invention in diagnostic techniques andimaging applications such as positron emission tomography (PET).

Compounds of the invention are useful for the treatment of diarrhoea,depression, urinary incontinence, various mental illnesses, cough, lungoedema, various gastro-intestinal disorders, spinal injury and drugaddiction, including the treatment of alcohol, nicotine, opioid andother drug abuse and for disorders of the sympathetic nervous system forexample hypertension.

Compounds of the invention are useful as an analgesic agent for useduring general anaesthesia and monitored anaesthesia care. Combinationsof agents with different properties are often used to achieve a balanceof effects needed to maintain the anaesthetic state (eg. Amnesia,analgesia, muscle relaxation and sedation). Included in this combinationare inhaled anaesthetics, hypnotica, anxiolytics, neuromuscular blockersand opioids.

The compounds of the present invention in isotopically labelled form areuseful as a diagnostic agent.

Also within the scope of the invention is the use of any of thecompounds according to the formula (I) above, for the manufacture of amedicament for the treatment of any of the conditions discussed above.

A further aspect of the invention is a method for the treatment of asubject suffering from any of the conditions discussed above, whereby aneffective amount of a compound according to the formula (I) above, isadministered to a patient in need of such treatment.

The best mode of performing the invention known at present, is to usethe compounds according to Example 1 (compound 7); Example 2 (compound9); Example 3 (compound 10); and Example 6 (compound 17). The numberingof the compounds is in accordance with the numbering in the Schemespresented in the following.

METHODS OF PREPARATION

The compounds of the present invention may be prepared as described inthe following.

General Procedure for the Preparation of 1,4-trans-cyclohexane DerivedCompounds

As shown in SCHEME I above, compounds of the formula (H) may be obtainedfrom compounds of the formula (G), by deprotection by methods known inthe art and exemplified in the literature, see e.g. Protecting groups byGreen, or Modern Synthetic Reactions by House, which are well known to aperson skilled in the art.

As shown in SCHEME I, compounds of the formula (G) may be obtained byreaction among an amine of the formula (F), and using a guanylatingreagent, an amidinating reagent or an alkylating reagent. Thesereactions may be performed in solvents such as THF, toluene, ether,dimethylformamide, dioxane, dichloromethane or in solvents mixtures.

As shown in SCHEME I, compounds of the formula (F) and (H) may beobtained from compounds of the formula (E), by deprotection of theN,N-dibenzyl group by methods known in the art and exemplified in theliterature, see, e.g. Protecting groups by Green, Modern SyntheticReactions by House, March, J., Advanced Organic Chemistry 4^(th) Ed.,John Wiley & Sons, 1992, which are well known to a person skilled in theart.

As shown in SCHEME I, compounds of the formula (E) may be obtained fromcompounds of the formula (D), and reacted with commercially availablealkyl isocyanate such as phenyl isocyanate or with dialkylcarbamoylchloride, prepared by methods known in the art literature (March, J.,Advanced Organic Chemistry 4 ^(th) Ed., John Wiley & Sons, 1992) or thelike in presence of a base such as triethylamine, Na₂CO₃,K₂CO₃,K₃PO₄,CsF, NaOH, DIPEA or the like. The reaction may be carried out insolvents such as THF, dichloromethane, toluene, ether,dimethylformamide, dioxane, or in solvents mixtures.

As shown in SCHEME I, compounds of the formula (D) may be obtained froma reduction of an amide of the formula (C). The reduction step may beperformed with a reducing agent commercially available such LiA1H₄, BH₃,NaBH₃CN or the like in the presence of solvent such as THF, dioxane,ether, dichloromethane toluene or in a solvents mixtures.

As shown in the SCHEME I, compounds of the formula (C) may be obtainedby reactions among a carbonyl compound of the formula (B) wherein X is asuitable leaving group such as chloro, bromo, hydroxy or the like, andwith an alkyl amine such as 2,2-diphenylethylamine andcyclohexanemethylamine or the like. The reaction may be performed insolvents such as THF, toluene, ether, dimethyl-formamide, dioxane,dichloromethane or solvents mixtures.

As shown in SCHEME I, compounds of the formula (B) may be obtained byprotecting a commercially available amine compound of the formula (A),by methods known in the art and exemplified in the literature, see e.g.Protecting groups by Green, or Modern Synthetic Reactions by House,followed by acid activation using a chloroformate such asisobutylchloroformate in a solvent such as THF.

In Scheme I above R¹, R², R³, R⁴, R⁵ and R⁵ are as defined in formula Iabove.

General Procedure for the Preparation of 1,4-cis,trans-cyclohexaneDerived Compounds

Compounds of the general formula N may be prepared by following theprocedure described in Scheme 2 below.

A commercially available cis/trans mixture of 1,4-bis-aminomethylcyclohexane (compound I) is converted into mono-(diBoc)-guanidinomethylderivative K using a protected guanylating reagent such as1-H-pyrazole-1-(N,N-bis(tert-butoxycarbonyl)carboxamidine in an organicsolvent such a THF.

The secondary amine (compound L) may be generated using a reductiveamination step, where compound K is treated with an aldehyde in thepresence of an acid such as acetic acid or ZnCl₂ in a protic solventsuch as methanol or ethanol in the presence of a reducing agent such assodium cyanoborohydride.

Compounds of the general formula M may be obtained by performing an ureareaction where compound L is reacted with a dialkylcarbamoyl chloridesuch as N-methyl-N-phenyl-carbamoylchloride in a solvent such asmethylene chloride and in the presence of a tertiary amine such astriethylamine or the like.

Finally, compound of the general formula N may be obtained by cleavageof the Boc protecting groups, using an acid such as trifluoroacetic acidor aqueous hydrochloric acid.

In Scheme I above R¹, R², and R³ are as defined in formula I above.

EXAMPLES

The invention will now be described in more detail by way of thefollowing Examples, which are not to be construed as limiting theinvention in any way.

Example 1 Preparation oftrans-1-N-(Cyclohexlmethyl)-N-(N-methyl-N-phenylcarbamoyl)-aminomethyl-4-aminomethyl Cyclohexane (Compound 7)

Compound 7 of Example 1 was prepared as follows.

Step 1

Preparation of trans-4,N,N-(Dibenzyl)-aminomethyl Cyclohexane CarboxylicAcid (Compound 2)

To a suspension of (40.0 g, 254 mmol) oftrans-4-(Aminomethyl)cyclohexanecarboxylic (compound 1) acid, in 1.5 Lof methanol was added benzaldehyde (60 ml, 590 mmol) followed by sodiumcyanoborohydride (16 g, 254 mmol). The pH was then adjusted to approx. 5with glacial acetic acid. The reaction was allowed to stir for 48 hrs,during which the pH is monitored and adjusted to 5 as needed, afterwhich the reaction volume was then decreased and the pH adjusted to 9with 1 N NaOH. The reaction was then extracted repeatedly with diethylether. The organic layers were combined, washed with brine, dried overNa₂SO₄, filtered and concentrated. The resulting product solidifies onstanding and was recrystallized from methanol giving 32 g of impurproduct which was used without further purification in the next step.

The monobenzyl was isolated as a white solid which formed during theextraction and was collected by filtration. (8.2 g)

Monobenzyl ¹H NMR: (D₂O) δ (ppm): 7.40-7.20 (5H, m, Ar), 4.06 (CH ₂Ar,5H, s), 2.75 (2H, d, J=7.2, NCH ₂), 1.95-1.85 (1H, m), 1.75-1.72 (2H,m), 1.64-1.62 (2H, m), 1.56-1.51 (1H, m), 1.22-1.11 (2H, m), 0.91-0.81(2H, m). ¹³ C NMR: (D₂O, DSS) δ (ppm): 31.43 (CH₂), 31.88 (CH₂), 36.81(CH), 48.95 (CH), 54.01 (NCH₂), 55.35 (NCH₂), 131.94 (CH), 132.37 (CH),132.60 (CH), 133.30 (C), 188.43 (C═O).

Step 2

Preparation of trans-1-N-(Cyclohexylmethyl)-4-N,N-(dibenzyl)-aminomethylCyclohexane Carboxamide (Compound 3)

To a solution of compound 2 prepared in the previous step 1 (2.18 g, 647mmol), in dry THF (10 ml) at −25° C., was added triethylamine (1.08 ml,7.76 mmol) followed by isobutylchloroformate (1.0 ml, 7.76 mmol). Thereaction mixture was stirred at −25° C. for 30 min. A white precipitatewas formed during the reaction.

The cyclohexanemethylamine (1.26 ml, 9.71 mmol) was added dropwise viasyringe. The reaction mixture was warmed up to r.t., stirred for 1 h,and then quenched with saturated aqueous NH₄Cl solution, and extractedwith CH₂Cl₂. The organic layer was dried over anhydrous MgSO₄ andconcentrated to give a crude product, which was further purified bysilica gel column chromatography using hexane-AcOEt (4:1″1:1) to providethe title product (compound 3), (1.86 g, 67%).

¹H NMR: (CDCl₃, TMS) δ (ppm): 7.36-7.20 (10H, m, Ar), 5.40 (1H, s, br,NH), 3.51 (4H, s, CH ₂Ph), 3.07 (2H, t, CH ₂N), 2.19 (2H, d, CH ₂N),2.20-1.87 (5H, m), 1.73-1.58 (8H, m), 1.44-1.41 (2H, m), 1.23-1.15 (2H,m), 0.92-0,90 (2H, m), 0.76-0,72 (2H, m)

Step 3

Preparation oftrans-1-N-(Cyclohexylmethyl)-aminomethyl-4-N,N-(dibenzyl)aminomethylCyclohexane (Compound 4)

To a solution of compound 3 (1.85 g, 4.28 mmol) prepared in the previousstep 2, in dry THF (20 ml) at r.t., was added slowly LAH (490 mg, 12.84mmol). The reaction mixture was heated at reflux 80° C. overnight. Themixture was then cooled down at r.t., quenched with MeOH until nohydrogen formation evolved and then 1 N HCl was added to dissolve theprecipitate. The gray mixture was extracted with CH₂Cl₂ and AcOEt. Theorganic layer was dried over anhydrous MgSO₄ and concentrated to give(1.2 g, 67% ) of white solid (compound 4).

¹H NMR: (CDCl₃, TMS) δ (ppm): 9.2 (1H, s, br, NH), 7.66 (4H, s, Ar),7.44 (6H, s, Ar), 4.54 (2H, s, br, CH ₂N), 4.14 (2H, s, br, CH ₂N), 2.75(6H, s, br, CH ₂Ph, CH ₂N), 1.99-1.90 (9H, m), 1.80-1.60 (4H, m),1.27-1.02 (6H, m), 0.83-0.80 (2H, m).

Step 4

Preparation oftrans-1-N-(Cyclohexylmethyl)-N-(N-phenylcarbamoyl)-aminomethyl-4-N,N-(dibenzyl)aminomethylcyclohexane(compound 5)

To a solution of (compound 4) (500 mg, 1.2 mmol) in dry THF (12 ml) andCH₂Cl₂ (3 ml) at r.t. was added triethylamine (167 μl, 1.2 mmol)followed by phenylisocyanate (195 μl, 1.79 mmol).

The reaction mixture was stirred 2 h at r.t., quenched with aqueousNH₄Cl solution then extracted with AcOEt. The organic layer was driedover anhydrous MgSO₄ and concentrated to give the crude product whichwas further purified by silica gel column chromatography usinghexane-AcOEt (9:1) to provide the title product (compound 5) (545 mg,84%).

¹H NMR: (CDCl₃, TMS) δ (ppm): 7.38-7.19 (15 H, m, Ar) 3.50 (4H, s,CH₂Ph), 3.15-3.11 (4H, m, CH ₂N), 2.19 (2H, d, CH ₂N), 1.93-1.90 (2H,m), 1.78-1.55 (9H, m), 1.28-1.18 (4H, m), 0.95-0.90 (4H, m), 0.76-0.70(2H, m).

Step 5

Preparation of trans-1-N-(Cyclohexylmethyl)-N-(N-methyl-N-phenylcarbamoyl)-aminomethyl 4-N,N-(dibenzyl)aminomethyl Cyclohexane (Compound6)

To a solution of (compound 5) (702 mg, 1.31 mmol) prepared in theprevious step 4, in dry THF (25 ml) at r.t., was added NaH 60% inmineral oil (1.56 mg, 3.92 mmol). The reaction mixture was stirred 30min then methyl iodide (243 μl, 3.92 mmol) was added dropwise viasyringe. The reaction mixture was stirred 1 h at r.t., quenched withaqueous NH₄Cl solution, and extracted with AcOEt. The organic layer wasdried over anhydrous MgSO₄ and concentrated to give the crude product,which was further purified by silica gel column chromatography usinghexane-AcOEt (85:15) to provide the title product (compound 6) as acolorless viscous oil (645 mg, 89%).

¹H NMR: (CDCl₃, TMS) δ (ppm): 7.37-7.04 (15H, m, Ar), 3.50 (4H, s, CH₂Ph), 3.15 (3H, s, CH ₃), 2.86-2.81 (4H, m, CH ₂N), 2.18 (2H, m, CH ₂N),1.90-1.86 (2H, m), 1.68-1.46 (9H, m), 1.26-1.13 (4H, m), 0.83-0.68 (6H,m).

Step 6

Preparation of trans-1-N-(Cyclohexylmethyl)-N-(N-methyl-N-phenylcarbamoyl)-aminomethyl-4-aminomethyl Cyclohexane (Compound 7)

The product (compound 6) (1.19 g, 2.16 mmol) prepared in the previousstep 5, was dissolved in AcOH (20 ml) and palladium on activated carbon10% (240 mg) was added to the solution. The mixture was stirredovernight with 60 psi of hydrogen, 4 h at 50° C. and 4 h at 70° C. Themixture was then cooled down and filtered over celite pad and thesolvent removed under reduced pressure. The crude product was dissolvedin CH₂Cl₂ and the organic phase washed with saturated aqueous NaHCO₃solution. The organic layer was dried over anhydrous MgSO₄ andconcentrated to give the pure desired product (compound 7) (795 mg, 99%)as a yellow viscous oil.

¹H NMR: (CDCl₃, TMS) δ (ppm): 7.35-7.23 (2H, m, Ar), 7.12-7.03 (3H, m,Ar), 3.16 (3H, s, CH ₃), 2.90-2.82 (4H, m, CH ₂N), 2.57-2.52 (2H, m, CH₂N), 1.90-150 (11H, m), 1.28-1.05 (6H, m), 0.93-0.79 (6H, m).

Example 2 Preparation oftrans-1-N-(cyclohexylmethyl)-N-(N-methyl-N-phenylcarbamoyl)-aminomethyl-4-guanidinomethylCyclohexane (Compound 9)

Compound 9 of Example 2 was prepared as follows.

Step 1

Preparation oftrans-1-N4cyclohexylmethyl)-N-(N-methyl-N-phenylcarbamoyl)-aminomethyl-4-(di-t-butylcarbonyloxy)-guanidinomethyl Cyclohexane (Compound 8)

To a solution of (compound 7) (459 mg, 1.24 mmol) prepared in Example 1,in dry THF (15 ml) at r.t., was added1-H-pyrazole-1-(N,N-bis(tert-butoxycarbonyl)carboxamidine) (413 mg, 1.48mmol). The mixture was stirred overnight and concentrated under reducedpressure. The crude product was purified by silica gel columnchromatography using hexane-AcOEt (9:1) to provide the desired product(compound 8) (548 mg, 76%) as a white foam.

¹H NMR: (CDCl₃, TMS) δ (ppm): 8.38 (1H, s, br, NH), 7.34-7.26 (2H, m,Ar), 7.13-7.05 (3H, m, Ar), 3.29-3.25 (2H, m, CH ₂N), 3.16 (3H, s, CH₃),2.89-2.83 (4H, m, CH ₂N), 1.81-1.78 (2H, m), 1.69-1.46 (27H, m,C(CH₃)₃), 1.26-1.13 (4H, m), 0.99-078 (6H, m).

Step 2

Preparation oftrans-1-N-(cyclohexylmethyl)-N-(N-methyl-N-phenylcarbamoyl)-aminomethyl-4-guanidinomethylCyclohexane (Compound 9)

To a solution of (compound 8) (548 mg, 0.89 mmol) prepared in theprevious step 1, in dry CH₂Cl₂ (5 ml), was added TFA (15 ml) at r.t. Thereaction mixture was stirred 2 days and concentrated under reducedpressure. The resulting mixture was dissolved in CH₂Cl₂ and washed withsaturated aqueous NaHCO₃ solution. The organic layer was dried overanhydrous MgSO₄ concentrated and the resulting mixture was purified bysilica gel column chromatography using MeOH-CH₂Cl₂ (9:1) to provide thedesired product (compound 9) (280 mg, 70%) as a light yellow oil.

¹H NMR: (CDCl₃, TMS) δ (ppm): 7.64 (1H, s, br, NH), 7.34-7.27 (2H, m,Ar), 7.14-7.03 (6H, m, Ar, NH), 3.13 (3H, s, CH ₃), 3.00 (2H, s, br, CH₂N), 2.87-2.80 (4H, m, CHN), 1.79-1.50 (12H, m), 1.21-0.78 (9H, m).

Example 3 Preparation oftrans-1-N-(4-chlorobenzyl)-N-(N-methyl-N-phenylcarbamoyl)-aminomethyl-4-guanidinomethylcyclohexane (compound 10)

By following the same procedure as described in Example 1, step 2 butsubstituting cyclohexanemethylamine for 4-chlorobenzoylamino followed bystep 3-6, and step 1-2 from Example 2, the compound (10) was alsoprepared.

¹H NMR (MeOD-d₄) δ 7.35 (m, 4H), 7.17 (m, 3H), 7.0 (t, 2H), 4.25 (s,2H), 3.15 (d, 3H), 3.0 (t, 3H), 2.85 (d, 2H), 1.85 (d, 2 H), 1.75 (d,2H), 1.6 (broad, 2H), 0.9 (m, 6H). MS: 442.24 (M+H).

Example 4 Preparation oftrans-1-[N-(2,2-diphenylethyl)-N-morpholine-carbamoyl]-aminomethyl-4-guanidinomethylCyclohexane Hydrochloride (Compound 11)

Compound 11 was obtained by following the procedure described forExample 1, step 4, but substituting phenylisocyanate for morpholinecarbamoyl chloride, and substituting compound 4 fortrans4-N-(diBoc)guanidinomethyl-1-N-(2,2-diphenylethyl)aminomethylcyclohexane, followed by cleavage of Boc-groups using the proceduredescribed in Example 2, step 2.

¹H NMR (CDCl₃) δ 8.4 (t, 1H) 7.15-7.35 (m, 10H), 4.35 (t, 1H), 3.85 (d,2H), 3.52 (t, 4H), 3.27 (t, 2H), 2.95 (d, 6H), 1.8 (m, 6H), 1.5 (d,18H), 0.85 (m, 4H). MS (APCI): 687.5 (M+H).

MS (APCI): 478.5.

Example 5 Preparation of1-N-(4-chlorobenzyl)-N-(N-methyl-N-phenylcarbamoyl)-aminomethyl-4-guanidinomethylCyclohexane (Compound 16)

Compound 16 of this Example was prepared by following the syntheticroute described in Scheme 4 below.

Step 1

Preparation of 4-aminomethyl-1-(diBoc)-guanidinomethyl Cyclohexane(Compound 13)

Part A

1-H-pyrazole-1-carboxamidine was prepared according to Bernatowicz et.al., J. Org. Chem. 1992, 57, pp.2497-2502, and protected withdi-tert-butyl dicarbonate to give1-H-pyrazole-1-(N,N-bis(tert-butoxycarbonyl)carboxamidine according toDrake et. al, Synth. 1994. pp.579-582.

Part B

Step 1

To a solution of 1,4-bis-aminomethyl-cyclohexane (compound 12) (20 g,0.14 mol) in THF (200 mL) was added a solution of1-H-Pyrazole-1-(N,N-bis(tert-butoxycarbonyl)carboxamidine (22.0 g, 0.07mol) in THF (100 mL). The solution was stirred at room temperature for 3hrs. The solvent was removed under reduced pressure to give a syrupyresidue which was taken up in ethyl acetate and washed with water untilneutral pH. The organic layer was washed with brine, dried over MgSO₄and concentrated. The product (compound 13) was purified by columnchromatography on silica gel using a mixture of methylenechloride:methanol as the eluent to afford 11.6 g (43% yield) of1-(diBoc)-guanidinomethyl-4-aminomethyl cyclohexane.

¹H NMR (CDCl₃) δ 3.26 (d of t, 2H), 2.52 (d of d, 2H), 1.82-0.97 (m,28H, with singlet at 1.5).

Step 2

Preparation of(1-N-4-chlorobenzyl)-aminomethyl-4-N-(diBoc)-guanidinomethyl Cyclohexane(Compound 14)

To a solution of 1-(diBoc)-guanidinomethyl-4-aminomethyl cyclohexane(compound 13) (1 eq) in methanol containing 1% (v/v) of glacial aceticacid (alternatively, ZnCl₂ can be used) was added 4-chlorobenzaldehyde(1 eq), followed by NaBH₃CN (3-4 eq). The reaction mixture was stirredat room temperature overnight. The reaction was quenched with water,basified with aqueous NaHCO₃ solution and extracted with methylenechloride. The organic layer was washed with brine, dried over MgSO₄ andconcentrated. The product (compound 14) was chromatographed on silicagel using a mixture of hexane:ethyl acetate as the eluent.

Step 3

Preparation of1-N-(4-chlorobenzyl)-N-(N-methyl-N-phenylcarbamoyl)-aminomethyl-4-N-(diBoc)-guanidinomethylCyclohexane (Compound 15)

To a solution of secondary amine (compound 14 Scheme 4) (1 eq) indioxane or methylene chloride was added triethylamine (1.5-2.0 eq),followed by the N-methyl-N-phenyl carbamoylchloride (1 eq). The reactionmixture was stirred at room temperature for 3 h overnight, then basifiedwith 1N K₂CO₃ solution and extracted with ethyl acetate. The organiclayer was washed with brine, dried over MgSO₄, concentrated andchromatographed on silica gel or purified by preparative TLC using amixture of hexane-ethyl acetate as the eluent.

Step 4

Preparation of1-N-(4-chlorobenzyl)-N-(N-methyl-N-phenylcarbamoyl)-aminomethyl-4-guanidinomethylCyclohexane (Compound 16)

The diBoc-guanidino compound (compound 15 Scheme 4) was dissolved in 4NHCl in dioxane or 50% trifluoroacetic acid in methylene chloride andstirred at room temperature for 2 h—overnight. The solvent was removedunder reduced pressure. The residue was dissolved in water andlyophylized. The product (compound 16 in Scheme 4) may also (whenappropriate) be purified by reversed-phase HPLC using acetonitrile-wateras the eluent.

¹H NMR (pyridine) δ 7.0-7.45 ( m, 9H), 4.35 (d, 2H), 3.35 (t, 2H), 3.15(s, 3H), 3.05 (d, 1H), 2.85 (d, 1H), 0.8-2.0 (m, 10H).

MS: 442.06 (M+H).

Example 6 Preparation of1-N-[(N-Methyl-N-Phenylcarbamoyl)-(1-naphthylmethyl)]aminomethyl-4-guanidinomethylCyclohexane (Compound 17)

Following the procedure described for the preparation of compound 16 ofExample 5, but using 1-naphtaldehyde in step 2 followed by step 3-4, thetitle compound 17 was obtained.

MS(APCI): 458.2 (M+H).

Example 7 Preparation of1-N-[(N-methyl-N-phenylcarbamoyl)-(2-naphthylmethyl]aminomethyl-4-guanidinomethylCyclohexane (Compound 18)

Following the procedure described for the preparation of compound 16 inExample 5, but using 2-naphtaldehyde in step 2 followed by step 3-4, thetitle compound 18 was obtained.

¹H NMR (pyridine) δ 7.95 (d, 2H), 7.0-7.7 (m, 10H), 4.55 (s, 2H), 3.25(s, 3H), 3.10 (m, 2H), 2.95 (d, 2H), 0.8-2.0 (m, 10H). MS(APCI): 442.01(M +H)

Example 8 Preparation ofN-(Cyclohexylmethyl)-N′-methyl-N′-phenyl-N-({4-[(3-pyridazinylamino)methyl]-cyclohexyl}methyl)urea(Compound 19)

Compound 7 (0.23 g, 0.62 mmol) was mixed with 3,6-dichloropyridazine andEt₃N (0.17 mL, 1.2 mmol) and heated in EtOH (2 mL) at 80° C. for 2 days.The solvent was evaporated and the residue purified by chromatography onsilica (0 to 100% EtOAc in heptane) to give 0.13 g solid. 0.11 g of thissolid was used for hydrogenolysis (H₂, 30 psi) with 20% palladiumhydroxide on carbon (Pearlmans catalyst) (100 mg) in methanol (10 mL)for 4 h at 25 ° C., filtration and evaporation of solvent was followedby chromatography on silica (0 to 5% MeOH in CH₂Cl₂) to give compound 19(32 mg, 12%).

¹H NMR (CDCl₃) δ 0.7-1.8 (m, 21H), 2.80 (m, 4H), 3.10 (s, 3H), 3.19 (m,2H), 4.83 (m, 1H), 6.56 (m, 1H), 7.00-7.30 (m, 6H), 8.47 (m, 1H). MS450.52 (M+H).

Example 9 Preparation of2-({[4-({(Cyclohexylmethyl)[(methylanilino)carbonyl]amino}methyl)cyclohexyl]-methyl}amino)-1-pyridiniumolate(Compound 20)

Compound 7 (0.23 g, 0.62 mmol) was mixed with 2-chloropyridine-N-oxidehydrochloride (0.21 g, 1.2 mmol) and Et₃N (0.17 mL, 1.2 mmol) and heatedin i-buOH (2 mL) at 100 ° C. for 2 days. Another portion of2-chloropyridine-N-oxide hydrochloride and Et₃N was added and heatingcontinued 2 days. The solvent was evaporated and the residue purified bychromatography on silica (0 to 10% MeOH in CH₂Cl₂) to give compound 20(0.11 g, 38%).

¹H NMR (CDCl₃) δ 0.7-1.9 (m, 21H), 2.85 (m, 4H), 3.10 (m, 2H), 3.18 (s,3H), 6.56 (m, 2H), 6.90 (m, 1H), 7.04-7.36 (m, 6H), 8.10 (m, 1H). MS465.50 (M+H).

Preparation ofN-(Cyclohexylmethyl)-N′-methyl-N-{[4-({[1-(methylsulfanyl)-2-nitroethenyl]-amino}methyl)cyclohexyl]methyl}-N′-phenylurea(Compound 21)

Compound 7 (0.48 g, 1.3 mmol) was mixed with1,1-bis(methylsulfanyl)-2-nitroethylene (0.24 g, 1.4 mmol) and heated inTHF (10 mL) at 70 ° C. After 4 h, another portion of1,1-bis(methylsulfanyl)-2-nitroethylene was added and heating continued12 h.The solvent was evaporated and the residue purified bychromatography on silica (0 to 10% MeOH in CH₂Cl₂) to give compound 21(0.60 g, 94%).

¹H NMR (CDCl₃) δ 0.7-1.8 (m, 21H), 2.38 (s, 3H), 2.81 (m, 4H), 3.11 (s,3H), 3.22 (m, 2H), 6.52 (s, 1H), 6.98-7.30 (m, 5H), 10.60 (s, 1H). MS489.50 (M+H).

Example 10 Preparation ofN-(Cyclohexylmethyl)-N′-methyl-N-{[4-({[1-(methylamino)-2-nitroethenyl]-amino}methyl)cyclohexyl]methyl}-N′-phenylurea(Compound 22)

Compound 21 (0.23 g, 0.47 mmol) was dissolved in a 2M solution of MeNH₂in MeOH (5 mL) and heated in a sealed tube at 80 ° C. for 3 h. Thesolvent was evaporated and the residue purified by chromatography onsilica (0 to 10% MeOH in CH₂Cl₂) to give compound 22 (0.15 g, 70%).

¹H NMR (CDCl₃) δ 0.7-1.9 (m, 21H), 2.85 (m, 4H), 3.11 (m, 2H), 3.16 (s,3H), 6.61 (s, 1H), 6.71, 6.85 (2m, 1H), 7.02-7.36 (m, 5H), 10.20 (s,1H). MS 472.49 (M+H).

Example 11 Preparation ofN-(Cyclohexylmethyl)-N′-methyl-N-[(4-{[(3-nitro-1H-pyrrol-2-yl)amino]methyl}-cyclohexyl)methyl]-N′-phenylurea(Compound 23)

Compound 21 (0.60 g, 1.2 mmol) and 2,2-diethoxy-1-ethanamine (0.35 mL,2.4 mmol) was dissolved in EtOH (10 mL) and heated in a sealed tube at80 ° C. for 12 h. The solvent was evaporated and the residue purified bychromatography on silica (0 to 10% MeOH in CH₂Cl₂) to give 0.67 g. 0.34g of this solid was refluxed in 0.05 N HCl for 2 h. Neutralisation andextraction with EtOAc gave a crude product wich was purified on silica(0 to 100% EtOAc in heptane to give compound 23 (35 mg, 12%)

¹H NMR (CDCl₃) δ 0.7-1.9 (m, 21H), 2.85 (m, 4H), 3.16 (s, 3H), 3.25 (m,2H), 6.16 (d, 1H), 6.42 (d, 1H), 7.02-7.36 (m, 5H), 7.69 (m, 1H), 9.60(s, 1H). MS 482.45 (M+H).

Pharmaceutical Compositions

The novel compounds according to the present invention may beadministered orally, intramuscularly, subcutaneously, topically,intranasally, intraperitoneally, intrathoracially, intravenously,epidurally, intrathecally, intracerebroventricularly and by injectioninto the joints.

A preferred route of administration is orally, intravenously orintramuscularly.

The dosage will depend on the route of administration, the severity ofthe disease, age and weight of the patient and other factors normallyconsidered by the attending physician, when determining the individualregimen and dosage level as the most appropriate for a particularpatient.

For preparing pharmaceutical compositions from the compounds of thisinvention, inert, pharmaceutically acceptable carriers can be eithersolid or liquid. Solid form preparations include powders, tablets,dispersible granules, capsules, cachets, and suppositories.

A solid carrier can be one or more substances which may also act asdiluents, flavoring agents, solubilizers, lubricants, suspending agents,binders, or tablet disintegrating agents; it can also be anencapsulating material.

In powders, the carrier is a finely divided solid which is in a mixturewith the finely divided active component. In tablets, the activecomponent is mixed with the carrier having the necessary bindingproperties in suitable proportions and compacted in the shape and sizedesired.

For preparing suppository compositions, a low-melting wax such as amixture of fatty acid glycerides and cocoa butter is first melted andthe active ingredient is dispersed therein by, for example, stirring.The molten homogeneous mixture is then poured into convenient sizedmolds and allowed to cool and solidify.

Suitable carriers are magnesium carbonate, magnesium stearate, talc,lactose, sugar, pectin, dextrin, starch, tragacanth, methyl cellulose,sodium carboxymethyl cellulose, a low-melting wax, cocoa butter, and thelike.

Pharmaceutically acceptable salts are acetate, benzenesulfonate,benzoate, bicarbonate, bitartrate, bromide, calcium acetate, camsylate,carbonate, chloride, citrate, dihydrochloride, edetate, edisylate,estolate, esylate, fumarate, glucaptate, gluconate, glutamate,glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide,hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate,lactobionate, malate, maleate, mandelate mesylate, methylbromide,methylnitrate, methylsulfate, mucate, napsylate, nitrate, pamoate(embonate), pantothenate, phosphate/diphosphate, polygalacturonate,salicylate, stearate, subacetate, succinate, sulfate, tannate, tartrate,teoclate, triethiodide, benzathine, chloroprocaine, choline,diethanolamine, ethylenediamine, meglumine, procaine, aluminium,calcium, lithium, magnesium, potassium, sodium, and zinc.

Preferred pharmaceutically acceptable salts are the hydrochlorides,trifluoroacetates and bitartrates.

The term composition is intended to include the formulation of theactive component with encapsulating material as a carrier providing acapsule in which the active component (with or without other carriers)is surrounded by a carrier which is thus in association with it.Similarly, cachets are included.

Tablets, powders, cachets, and capsules can be used as solid dosageforms suitable for oral administration.

Liquid from compositions include solutions, suspensions, and emulsions.Sterile water or water-propylene glycol solutions of the activecompounds may be mentioned as an example of liquid preparations suitablefor parenteral administration. Liquid compositions can also beformulated in solution in aqueous polyethylene glycol solution.

Aqueous solutions for oral administration can be prepared by dissolvingthe active component in water and adding suitable colorants, flavoringagents, stabilizers, and thickening agents as desired. Aqueoussuspensions for oral use can be made by dispersing the finely dividedactive component in water together with a viscous material such asnatural synthetic gums, resins, methyl cellulose, sodium carboxymethylcellulose, and other suspending agents known to the pharmaceuticalformulation art.

Preferably the pharmaceutical compositions is in unit dosage form. Insuch form, the composition is divided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofthe preparations, for example, packeted tablets, capsules, and powdersin vials or ampoules. The unit dosage form can also be a capsule,cachet, or tablet itself, or it can be the appropriate number of any ofthese packaged forms.

BIOLOGICAL EVALUATION A) In Vitro Model

Cell Culture

Human 293S cells expressing cloned human μ, δ, and κ receptors andneomycin resistance were grown in suspension at 37° C. and 5% CO₂ inshaker flasks containing calcium-free DMEM10% FBS, 5% BCS, 0.1% PluronicF-68, and 600 μg/ml geneticin.

Membrane Preparation

Cells were pelleted and resuspended in lysis buffer (50 mM Tris, pH 7.0,2.5 mM EDTA, with PMSF added just prior to use to 0.1 mM from a 0.1 Mstock in ethanol), incubated on ice for 15 min, then homogenized with apolytron for 30 sec. The suspension was spun at 100 g (max) for 10 minat 4° C. The supernatant was saved on ice and the pellets resuspendedand spun as before. The supernatants from both spins were combined andspun at 46,000 g(max) for 30 min. The pellets were resuspended in coldTris buffer (50 mM Tris/Cl, pH 7.0) and spun again. The final pelletswere resuspended in membrane buffer (50 mM Tris, 0.32 M sucrose, pH7.0). Aliquots (1 ml) in polypropylene tubes were frozen in dryice/ethanol and stored at −70° C. until use. The protein concentrationswere determined by a modified Lowry assay with SDS.

Binding Assays

Membranes were thawed at 37° C., cooled on ice, passed 3 times through a25-gauge needle, and diluted into binding buffer (50 mM Tris, 3 mMMgCl₂, 1 mg/ml BSA (Sigma A-7888), pH 7.4, which was stored at 4° C.after filtration through a 0.22 m filter, and to which had been freshlyadded 5 μg/ml aprotinin, 10 μM bestatin, 10 μM diprotin A, no DTT).Aliquots of 100 μl (for μg protein, see Table 1) were added to iced12×75 mm polypropylene tubes containing 100 μl of the appropriateradioligand (see Table 1) and 100 μl of test peptides at variousconcentrations. Total (TB) and nonspecific (NS) binding were determinedin the absence and presence of 10 μM naloxone respectively. The tubeswere vortexed and incubated at 25° C. for 60-75 min, after which timethe contents are rapidly vacuum-filtered and washed with about 12ml/tube iced wash buffer (50 mM Tris, pH 7.0, 3 mM MgCl₂) through GF/Bfilters (Whatman) presoaked for at least 2h in 0.1% polyethyleneimine.The radioactivity (dpm) retained on the filters was measured with a betacounter after soaking the filters for at least 12h in minivialscontaining 6-7 ml scintillation fluid. If the assay is set up in96-place deep well plates, the filtration is over 96-place PEI-soakedunifilters, which were washed with 3×1 ml wash buffer, and dried in anoven at 55° C. for 2h. The filter plates were counted in a TopCount(Packard) after adding 50 μl MS-20 scintillation fluid/well.

Data Analysis

The specific binding (SB) was calculated as TB-NS, and the SB in thepresence of various test peptides was expressed as percentage of controlSB. Values of IC₅₀ and Hill coefficient (n_(H)) for ligands indisplacing specifically bound radioligand were calculated from logitplots or curve fitting programs such as Ligand, GraphPad Prism,SigmaPlot, or ReceptorFit. Values of K₁ were calculated from theCheng-Prussoff equation. Mean±S.E.M. values of IC₅₀, K_(i) and n_(H)were reported for ligands tested in at least three displacement curves.

Receptor Saturation Experiments

Radioligand K_(δ) values were determined by performing the bindingassays on cell membranes with the appropriate radioligands atconcentrations ranging from 0.2 to 5 times the estimated K_(δ) (up to 10times if amounts of radioligand required are feasable). The specificradioligand binding was expressed as pmole/mg membrane protein. Valuesof K_(δ) and B_(max) from individual experiments were obtained fromnonlinear fits of specifically bound (B) vs. nM free (F) radioligandfrom individual according to a one-site model.

B) Biological Model (In Vivo Model) Freund's Complete Adjuvant (FCA),And Sciatic Nerve Cuff Induced Mechano-Allodynia in Rat

Animals

Male Sprague-Dawley rats (Charles River, St-Constant, Canada) weighing175-200 g at the time of surgery were used. They were housed in groupsof three in rooms thermostatically maintained at 200° C. with a 12:12 hrlight/dark cycle, and with free access to food and water. After arrival,the animals were allowed to acclimatize for at least 2 days beforesurgery. The experiments were approved by the appropriate MedicalEthical Committee for animal studies.

EXPERIMENTAL PROCEDURE Freund's Complete Adjuvant

The rats were first anesthetized in a Halothane chamber after which 10μl of FCA was injected s.c. into the dorsal region of the left foot,between the second and third external digits. The animals were thenallowed to recover from anesthesia under observation in their home cage.

Sciatic Nerve Cuff

The animals were prepared according to the method described by Mosconiand Kruger (1996). Rats were anesthetized with a mixture ofKetamine/Xylazine i.p. (2ml/kg) and placed on their right side and anincision made over, and along the axis of, the lateral aspect of theleft femur. The muscles of the upper quadriceps were teased apart toreveal the sciatic nerve on which a plastic cuff (PE-60 tubing, 2 mmlong) was placed around. The wound was then closed in two layers with3-0 vicryl and silk sutures.

Determination Of Mechano-Allodynia Using Von Frey Testing

Testing was performed between 08:00 and 16:00h using the methoddescribed by Chaplan et al. (1994). Rats were placed in Plexiglas cageson top of a wire mesh bottom which allowed access to the paw, and wereleft to habituate for 10-15 min. The area tested was the mid-plantarleft hind paw, avoiding the less sensitive foot pads. The paw wastouched with a series of 8 Von Frey hairs with logarithmicallyincremental stiffness (0.41, 0.69, 1.20, 2.04, 3.63, 5.50, 8.51, and15.14 grams; Stoelting, Ill., USA). The von Frey hair was applied fromunderneath the mesh floor perpendicular to the plantar surface withsufficient force to cause a slight buckling against the paw, and heldfor approximately 6-8 seconds. A positive response was noted if the pawwas sharply withdrawn. Flinching immediately upon removal of the hairwas also considered a positive response. Ambulation was considered anambiguous response, and in such cases the stimulus was repeated.

Testing Protocol

The animals were tested on postoperative day 1 for the FCA-treated groupand on post-operative day 7 for the Sciatic Nerve Cuff group. The 50%withdrawal threshold was determined using the up-down method of Dixon(1980). Testing was started with the 2.04 g hair, in the middle of theseries. Stimuli were always presented in a consecutive way, whetherascending or descending. In the absence of a paw withdrawal response tothe initially selected hair, a stronger stimulus was presented; in theevent of paw withdrawal, the next weaker stimulus was chosen. Optimalthreshold calculation by this method requires 6 responses in theimmediate vicinity of the 50% threshold, and counting of these 6responses began when the first change in response occurred, e.g. thethreshold was first crossed. In cases where thresholds fell outside therange of stimuli, values of 15.14 (normal sensitivity) or 0.41(maximally allodynic) were respectively assigned. The resulting patternof positive and negative responses was tabulated using the convention,X=no withdrawal; O=withdrawal, and the 50% withdrawal threshold wasinterpolated using the formula:

50% g threshold=10^((Xf+kδ))/10,000

where Xf=value of the last von Frey hair used (log units); k=tabularvalue (from Chaplan et al. (1994)) for the pattern of positive/negativeresponses; and δ=mean difference between stimuli (log units). Hereδ=0.224.

Von Frey thresholds were converted to percent of maximum possible effect(% MPE), according to Chaplan et al. 1994. The following equation wasused to compute % MPE:

${\% \quad {MPE}} = {\frac{{{Drug}\quad {treated}\quad {threshold}\quad (g)} - {{allodynia}\quad {threshold}\quad (g)}}{{{Control}\quad {threshold}\quad (g)} - {{allodynia}\quad {threshold}\quad (g)}} \times 100}$

Administration Test Substance

Rats were injected (subcutaneously, intraperitoneally, or orally) with atest substance prior to von Frey testing, the time betweenadministration of test compound and the von Frey test varied dependingupon the nature of the test compound.

What is claimed is:
 1. A compound according to formula I:

wherein: m and n are each independently an integer from 1-3, and one ormore of the hydrogens in the alkylene chain may optionally besubstituted by any one of a C₁-C₆ alkyl; a C₁-C₆ alkoxy; or a hydroxy;or one or more of the methylene groups may optionally be substituted bya heteroatom selected from O, N or S; R¹ is selected from hydrogen; abranched or straight C₁-C₆ alkyl; a C₂-C₆ alkenyl; a C₃-C₈ cycloalkyl; aC₄-C₈(alkyl-cycloalkyl) wherein the alkyl is a C₁-C₂ alkyl and thecycloalkyl is a C₃-C₆ cycloalkyl; R² is selected from any of: (i)hydrogen; (ii) a straight or branched C₁-C₆ alkyl; a C₂-C₆ alkenyl; or aC₂-C₆ alkynyl; (iii) a ((CH₂)_(q)-aryl); (iv) a ((CH₂)_(r)-heteroaryl)wherein the heteroaryl has from 5 to 10 atoms, each heteroatom beingselected from any of S, N and O; and wherein the heteroaryl mayoptionally and independently be substituted by 1 or 2 substituents Y,wherein each Y is as defined below; and wherein q and r are eachindependently an integer from 0 to 3; (v) a C₃-C₁₀ cycloalkyl,optionally comprising one or more unsaturations and optionallysubstituted by one or more heteroaryls, wherein each heteroaryl has from5 to 10 atoms and each heteroatom is selected from any of S, N and O;and wherein an aryl or heteroaryl may optionally and independently besubstituted by 1 or 2 substituents Y, wherein each Y is as definedbelow; (vi) a heteroaryl having from 5 to 10 atoms, each heteroatombeing selected from any of S, N and O; wherein the heteroaryl mayoptionally and independently be substituted by 1 or 2 substituents Y,wherein each Y is as defined below; or R¹ and R² may optionally form aheterocyclic ring, which may optionally be saturated or unsaturated; R³is selected from any one of: (i) hydrogen; (ii) a straight or branchedC¹-C₆ alkyl; C₂-C₆ alkenyl; or C₂-C₆ alkynyl; (iii) a C₆-C₁₀ arylalkyl,wherein the aryl may optionally be substituted by one or moreheteroaryls having from 5 to 10 atoms, each heteroatom being selectedfrom any of S, N and O; and wherein the aryl and heteroaryl mayoptionally and independently be substituted by 1 or 2 substituents Y,wherein each Y is as defined below; (iv) a heteroaryl-(C₅-C₁₀ alkyl),wherein the heteroaryl has from 5 to 10 atoms, each heteroatom beingselected from any of S, N, O, and wherein the heteroaryl may optionallyand independently be substituted by 1 or 2 substituents Y, wherein eachY is as defined below; (v) a C₃-C₁₀ cycloalkyl, optionally comprisingone or more unsaturations and optionally substituted by one or moreheteroaryls having from 5 to 10 atoms, each heteroatom being selectedfrom any of S, N and O, and wherein the aryl and heteroaryl mayoptionally and independently be substituted by 1 or 2 substituents Y,wherein each Y is as defined below; (vi) a (C₃-C₆ cycloalkyl-(CH₂)_(q))wherein q is an integer from 1 to 3; R₄ is selected from: (i) hydrogen;(ii) a straight or branched C₁-C₆ alkyl; C₂C₆ alkenyl; or C₂-C₆ alkynyl;(iii) a C₆-C₁₀ arylalkyl, wherein the aryl may optionally be substitutedby one or more heteroaryls having from 5 to 10 atoms, each heteroatombeing selected from any of S, N and O; and wherein the aryl andheteroaryl may optionally and independently be substituted by 1 or 2substituents Y, wherein each Y is as defined below; (iv) aheteroaryl-(C₅-C₁₀ alkyl), wherein the heteroaryl has from 5 to 10atoms, each heteroatom being selected from any of S, N and O, andwherein the heteroaryl may optionally and independently be substitutedby 1 or 2 substituents Y, wherein each Y is as defined below; (v) aC₃-C₁₀ cycloalkyl, optionally comprising one or more unsaturations andoptionally substituted by one or more heteroaryls wherein eachheteroaryl has from 5 to 10 atoms and each heteroatom is selected fromany of S, N and O; and wherein an aryl or heteroaryl may optionally andindependently be substituted by 1 or 2 substituents Y, wherein each Y isas defined below; (vi) a heteroaryl having from 5 to 10 atoms, eachheteroatom being selected from any of S, N and O; wherein the heteroarylmay optionally and independently be substituted by 1 or 2 substituentsY, wherein each Y is as defined below; R⁵ is selected from any one of:(i) hydrogen; (ii) a straight or branched C₁-C₆ alkyl; C₂-C₆ alkenyl; orC₂-C₆ alkynyl; (iii) a C₆-C₁₀ arylalkyl, wherein the aryl may optionallybe substituted by one or more heteroaryls having from 5 to 10 atoms,each heteroatom being selected from any of S, N and O; and wherein thearyl and heteroaryl may optionally and independently be substituted by 1or 2 substituents Y, wherein each Y is as defined below; (iv) aheteroaryl-(C₅-C₁₀ alkyl), wherein the heteroaryl has from 5 to 10atoms, each heteroatom being selected from any S, N and O, and whereinthe heteroaryl may optionally and independently be substituted by 1 or 2substituents Y, wherein each Y is as defined below; (v) a C₃-C₁₀cycloalkyl, optionally comprising one or more unsaturations andoptionally substituted by one or more heteroaryls having from 5 to 10atoms, each heteroatom being selected from any of S, N and O, andwherein an aryl or heteroaryl may optionally and independently besubstituted by 1 or 2 substituents Y, wherein each Y is as definedbelow; (vi) a heteroaryl having from 5 to 10 atoms, each heteroatombeing selected from any of S, N and O, wherein the heteroaryl mayoptionally and independently be substituted by 1 or 2 substituents Y,wherein each Y is as defined below;

 wherein R⁷, R⁸, R⁹, R¹⁰ and R¹¹ are each independently selected from:(a) hydrogen; (b) a straight or branched C₁-C₆ alkyl; C₂-C₆ alkenyl; orC₂-C₆ alkynyl; (c) a C₆-C₁₀ arylalkyl, wherein the aryl may optionallybe substituted by one or more heteroaryls having from 5 to 10 atoms,each heteroatom being selected from any of S, N and O, and wherein thearyl and heteroaryl may optionally and independently be substituted by 1or 2 substituents Y, wherein each Y is as defined below; (d) aheteroaryl-C₅-C₁₀ alkyl), wherein the heteroaryl has from 5 to 10 atoms,each heteroatom being selected from any of S, N and O, and wherein theheteroaryl may optionally and independently be substituted by 1 or 2substituents Y, wherein each Y is as defined below; (e) a C₃-C₁₀cycloalkyl, optionally comprising one or more unsaturations andoptionally substituted by one or more heteroaryls, each heteroarylhaving from 5 to 10 atoms, and each heteroatom being selected from anyof S, N and O; and wherein an aryl or heteroaryl may optionally andindependently be substituted by 1 or 2 substituents Y, wherein each Y isas defined below;

or R⁴ and R⁵ may optionally form a heterocyclic ring, which mayoptionally be saturated or unsaturated; Y is each and independentlyselected from any of CH₃; —(CH₂)_(p1) CF₃; halogen; C₁-C₃ alkoxy;hydroxy; —NO₂; —OCF₃; —CONR^(a)R^(b); —COOR^(a); —COR^(a);—(CH₂)_(p2)NR^(a)R^(b); —(CH₂)_(p3)CH3; (CH₂)_(p4)SOR^(a)R^(b);—(CH₂)_(p6)SO₂R^(a); (CH₂)_(p6)SO₂NR^(a); C₄-C₈(alkyl-cycloalkyl),wherein the alkyl is a C₁-C₂ alkyl and the cycloalkyl is a C₃-C₆cycloalkyl; 1 or 2 heteroaryls having from 5 to 10 atoms, eachheteroatom being selective from any of S, N and O; and oxides selectedfrom N-oxides or sulfoxides; and wherein: R^(a) and R^(b) are eachindependently selected from hydrogen; a branched or straight C₁-C₆alkyl; a C₁-C₆ alkenyl; a C₃-C₈ cycloalkyl; and wherein p1, p2, p4, p5are p6 are each and independently 0, 1 or 2; and p3 is 1 or 2; as wellas pharmaceutically acceptable salts of the compound of formula I andisomers, hydrates, isoforms and prodrugs thereof.
 2. A compoundaccording to formula I of claim 1, wherein: m=n=1; R¹ is selected fromhydrogen and a C₁-C₆ alkyl; R² is selected from: (i) hydrogen; (ii) aC₆-C₁₀ aryl, optionally and independently substituted by one or moreheteroaryls having from 5 to 10 atoms, each heteroatom being selectedfrom any of S, N and O, and wherein each heteroaryl may optionally andindependently be substituted by 1 or 2 substituents Y, wherein each Y isas defined in claim 1; (iii) a C₁-C₆ alkyl; or (iv) a C₃-C₁₀ cycloalkyl,optionally comprising one or more unsaturations and optionallysubstituted by one or more heteroaryls having from 5 to 10 atoms, eachheteroatom being selected from any of S, N and O, and wherein an aryl orheteroaryl may optionally and independently be substituted by 1 or 2substituents Y, wherein each Y is as defined in claim 1; R³ is selectedfrom: (i) hydrogen; (ii) a C₆-C₁₀ arylalkyl, wherein the aryl mayoptionally be substituted by one or more heteroaryls having from 5 to 10atoms, each heteroatom being selected from any of S, N and O, andwherein an aryl or heteroaryl may optionally and independently besubstituted by 1 or 2 substituents Y, wherein each Y is as defined inclaim 1; (iii) —(C₃-C₆ cycloalkyl-(CH₂)_(q)) wherein q is an integerfrom 1 to 3; R⁴ is hydrogen; R⁵ is selected from any one of: (i)hydrogen; (ii) a straight or branched C₁-C₆ alkyl; C₂-C₆ alkenyl; orC₂-C₆ alkynyl; (iii) a C₆-C₁₀ arylalkyl, wherein the aryl may optionallybe substituted by one or more heteroaryls having from 5 to 10 atoms,each heteroatom being selected from any of S, N and O; and wherein anaryl or heteroaryl may optional and independently be substituted 1 or 2substituents Y, wherein each Y is as defined claim 1; (iv) aheteroaryl-(C₅-C₁₀ alkyl), wherein the heteroaryl has from 5 to 10atoms, each heteroatom being selected from any of S, N and O, andwherein the heteroaryl may optionally and independently be substituted 1or 2 substituents Y, wherein each Y is as defined in claim 1; (v) aC₃-C₁₀ cycloalkyl, optionally comprising one or more unsaturations andoptionally substituted by one or more heteroaryls having from 5 to 10atoms, each heteroatom being selected from any of S, N and O, andwherein an aryl or heteroaryl may optionally and independently besubstituted by 1 or 2 substituents Y, wherein each Y is as defined inclaim 1; (vi) a heteroaryl having from 5 to 10 atoms, each heteroatombeing selected from any of S, N and O, wherein the heteroaryl mayoptionally and independently be substituted by 1 or 2 substituents Y,wherein each Y is as defined in claim 1;

 wherein R⁷, R⁸, R⁹, R¹⁰, R¹¹ are each independently selected from: (a)hydrogen; (b) a straight or branched C₁-C₆ alkyl; C₂-C₆ alkenyl; orC₂-C₆ alkynyl; (c) a C₆-C₁₀ arylalkyl, wherein the aryl may optionallybe substituted by one or more heteroaryls having from 5 to 10 atoms,each heteroatom being selected from any of S, N and O, and wherein anaryl or heteroaryl may optionally and independently be substituted by 1or 2 substituents Y, wherein each Y is as defined in claim 1; (d) aheteroaryl-(C₅-C₁₀ alkyl), wherein the heteroaryl has from 5 to 10atoms, each heteroatom being selected from any of S, N and O, andwherein the heteroaryl may optionally and independently be substitutedby 1 or 2 substituents Y, wherein each Y is as defined in claim 1; (e) aC₃-C₁₀ cycloalkyl, optionally comprising one or more unsaturations andoptionally substituted by one or more heteroaryls, each heteroarylhaving from 5 to 10 atoms, each heteroatom being selected from any of S,N and O, and wherein an aryl or heteroaryl may optionally andindependently be substituted by 1 or 2 substituents Y, wherein each Y isas defined in claim 1;

or R₄ and R₅ may optionally form a heterocyclic ring, which mayoptionally be saturated or unsaturated.
 3. A compound according to claim1, which compound is any one selected from
 2.


4. A compound according to any one of claim 3, 1, or 2 wherein saidcompound is in the form of a hydrochloride, sulfate, tartrate or citratesalt.
 5. A compound according to any one of claim 3, 1, or 2, whereinsaid compound is isotopically labeled.
 6. A compound of the formula (D)

wherein R³ is selected from any one of (i) hydrogen (ii) a straight orbranched C₁-C₆ alkyl, C₂-C₆ alkenyl or C₂-C₆ alkynyl; (iii) C₆-C₁₀arylalkyl, wherein the aryl may optionally be substituted by one or moreheteroaryls having from 5 to 10 atoms and the heteroatom is selectedfrom any of S, N and O; and wherein the aryl and heteroaryl mayoptionally and independently be substituted by 1 or 2 substituents Y;(iv) heteroaryl-(C₅-C₁₀alkyl), where the heteroaryl has from 5 to 10atoms and the heteroatom is selected from any of S, N and O, and whereinthe heteroaryl may optionally and independently be substituted by 1 or 2substituents Y; (v) C₃-C₁₀ cycloalkyl optionally comprising one or moreunsaturations and optionally substituted by one or more heteroarylshaving from 5 to 10 atoms and the heteroatom is selected from any of S,N and O, and wherein the aryl and heteroaryl may optionally andindependently be substituted by 1 or 2 substituents Y; (vi) ((C₃-C₆cycloalkyl)-(CH₂)_(q)) where q is an integer of from 1 to 3; and Y iseach and independently selected from any of CH₃; —(CH₂)_(p1) CF₃;halogen; C_(1-C) ₃ alkoxy; hydroxy; —NO2; —OCF₃; —CONR^(a)R^(b);—COOR^(a); —COR^(a); —(CH₂)_(p2)NR^(a)R^(b); —(CH₂)_(p3)CH₃;(CH₂)_(p4)SOR^(a)R^(b); —(CH₂)_(p5)SO₂R^(a); —(CH₂)_(p6)SO₂NR^(a);C₄-C₈(alkyl-cycloalkyl), wherein the alkyl is a C₁-C₂ alkyl and thecycloalkyl is a C₃-C₆ cycloalkyl; 1 or 2 heteroaryls having from 5 to 10atoms, each heteroatom being selective from any of S, N and O; andoxides selected from N-oxides or sulfoxides; and wherein R^(a) and R^(b)are each independently selected from hydrogen; a branched or straightC₁-C₆ alkyl; a C₁-C₆ alkenyl; a C₃-C₈ cycloalkyl; and wherein p1, p2,p4, p5 are p6 are each and independently 0, 1 or 2; and p3 is 1 or
 2. 7.A compound of the formula (F)

wherein R¹ is selected from hydrogen, a branched or straight C₁-C₆alkyl, C₁-C₆ alkenyl, C₃-C₈ cycloalkyl, C₄-C₈(alkyl-cycloalkyl) whereinthe alkyl is C₁ ₂ alkyl and the cycloalkyl is C₃-C₆ cycloalkyl; R² isselected from any of (i) hydrogen; (ii) a straight or branched C₁-C₆alkyl, C₂-C₆ alkenyl or C₂-C₆ alkynyl; (iii) —(CH₂)_(q)-aryl); (iv)—(CH₂)_(r) heteroaryl) where the heteroaryl has from 5 to 10 atoms andthe heteroatom is selected from any of S, N and O; and wherein theheteroaryl may optionally and independently be substituted by 1 or 2substituents Y where each Y is as defined in claim 1; and wherein q andr is each and independently an integer from 0 to 3; (v) C₃-C₁₀cycloalkyl, optionally comprising one or more unsaturations andoptionally substituted by one or more heteroaryls where the heteroarylhas from 5 to 10 atoms and the heteroatom is selected from any of S, Nand O; and wherein the heteroaryl may optionally and independently besubstituted by 1 or 2 substituents Y where each Y is as defined in claim1; (vi) heteroaryl having from 5 to 10 atoms, the heteroatom beingselected from any of S, N and O; wherein the heteroaryl may optionallyand independently be substituted by 1 or 2 substituents Y wherein each Yis as defined in claim 1; or R¹ and R² may optionally form aheterocyclic ring; R³ is selected from any one of (i) hydrogen; (ii) astraight or branched C₁-C₆ alkyl, C₂-C₆ alkenyl or C₂-C₆ alkynyl; (iii)C₆-C₁₀ arylalkyl, wherein the aryl may optionally be substituted by oneor more heteroaryls having from 5 to 10 atoms and the heteroatom isselected from any of S, N and O; and wherein the aryl or heteroaryl mayoptionally and independently be substituted by 1 or 2 substituents Ywherein each Y is as defined in claim 1; (iv) heteroaryl-(C₅-C₁₀ alkyl),where the heteroaryl has from 5 to 10 atoms and the heteroatom isselected from any of S, N and O, and wherein the heteroaryl mayoptionally and independently be substituted by 1 or 2 substituents Ywhere each Y is as defined in claim 1; (v) C₃-C₁₀ cycloalkyl, optionallycomprising one or more unsaturations and optionally substituted by oneor more heteroaryls having from 5 to 10 atoms and the heteroatom isselected from any of S, N and O, and wherein the aryl or heteroaryl mayoptionally and independently be substituted by 1 or 2 substituents Ywhere each Y is as defined in claim 1; (vi) —(C₃-C₆cycloalkyl)-(CH₂)_(q)) where q is an integer of from 1 to
 3. 8. A methodfor the treatment of a patient for pain, comprising administering tosaid patient an effective amount of a compound of the formula Iaccording to claim
 1. 9. A method for the treatment of a patient for agastrointestinal disorder, comprising administering to said patient aneffective amount of a compound of formula I according to claim
 1. 10. Amethod for the treatment of a patient for a spinal injury, comprisingadministering to said patient an effective amount of a compound offormula I according to claim
 1. 11. A compound according to either claim1 or claim 2, wherein: m=n=1; R¹ is selected from: (i) hydrogen; and(ii) methyl; R² is selected from: (i) hydrogen; (ii) phenyl; (iii) aC₁-C₃ alkyl; (iv) C₃-C₆ cycloalkyl; or R¹ and R² together form a ring offrom 4 to 6 atoms selected from C, N and O; R³ is selected from: (i)hydrogen; (ii) —CH₂-cyclohexyl; (iii) —CH₂-phenyl, optionallysubstituted by one or two halogens; (iv) —CH₂-naphthyl; R⁴ is hydrogen;R⁵ is selected from: (i) hydrogen;

(iv) a heteroaryl having from 5 to 10 atoms, each heteroatom beingselected from any of S, N and O, wherein the heteroaryl may optionallyand independently be substituted by 1 or 2 substituents, Y, wherein eachY is as defined in claim
 1. 12. A method of diagnosing a diseasecharacterized by the degeneration or dysfunction of opioid receptors,comprising administering to a subject an effective amount of theisotopically labeled compound of claim
 5. 13. A process for thepreparation of a compound of formula I according to claim 1, comprising:(a) protecting an amine of formula (A):

(b) subjecting the protected compound of step (a) to amidation toproduce a compound of formula (C):

(c) reducing said compound of formula (C); (d) reacting the product ofstep (c) with a dialkylcarbamoyl chloride, to produce a compound offormula (E):

(e) deprotecting the N,N-dibenzyl group in said compound of formula (E);(f) guanylating, amidating or alkylating the compound of step (e) toproduce a compound of formula (G):

 wherein R¹, R², R³, R⁴, and R⁵ in formulas (A), (C), (E), and (G) areas defined in formula I of claim
 1. 14. A process for the preparation ofa compound of formula I according to claim 11, comprising: (a)converting a cis/trans-mixture of 1,4-bis-aminomethyl cyclohexane into amono-(di-Boc)-guanidinomethyl derivative using a protected guanylatingreagent; (b) reductively aminating the product of step (a); (c) treatingthe product of step (b) with an aldehyde, R³CHO, to produce a compoundof formula (L):

(d) reacting said compound of formula (L) with adialkyl-carbamoylchloride in the presence of a tertiary amine to producea compound of formula (M):

(e) deprotecting the Boc-protecting groups in said compound of formula(M) to produce a cis,trans-guanidinomethyl cyclohexane compound offormula (N):

 wherein R¹, R², and R³ in formulas (L), (M) and (N) are as defined informula I of claim
 1. 15. A pharmaceutical composition comprising acompound of the formula I according to claim 1 as an active ingredient,together with a pharmacologically and pharmaceutically acceptablecarrier.